A heart defect is the most common congenital malformation, every 100th child is born with it. These genetic disorders include subsets of inherited arrhythmias, cardiomyopathies, vascular diseases and/or structural heart defects with heterogeneous clinical presentations, variable penetrance and expression, making identification of the disease-causing genes challenging.
In a global effort, researchers from the Helmholtz Center Munich and the International Mouse Phenotyping Consortium (IMPC) have screened 3,894 single-gene null mouse lines for structural and functional cardiac abnormalities. The study has now been published in “Nature Cardiovascular Research”.
As a result, the team of scientists have discovered that 705 genes when deleted induced cardiac arrhythmias, myocardial hypertrophy and/or ventricular dilatation. Unexpectedly, 486 of those genes are novel with no link to cardiac dysfunction in humans. These genes offer an unexplored genetic landscape and are an important starting point to validate human sequencing studies and expand detailed downstream molecular studies.
Mouse and human heart are anatomically remarkably similar throughout development, which is why mouse models are highly valued in the study of congenital heart defects. In an intensive phenotyping effort, this group has applied in-vivo electrocardiography and transthoracic echocardiography in young adult mice and ex-vivo microCT imaging in mouse embryos. Different routes of exploration such as downstream web-based analyses, UK Biobank and the NIC pediatric study, allowed the translational alignment to congenital, monogenetic forms of electrical conduction system disorders, cardiomyopathies and structural defects of the heart. Novel association of five genes to structural defects in the heart were observed for Casz1, Dnajc18, Pde4dip, Rnf38, and Tmem161. These five genes have previously only been categorized as “variants of unknown significance” in large sequencing studies of congenital heart defect patients. In close collaboration with clinicians of the German Centre for Cardiovascular Research (DZHK) will be sought to align and deepen the information obtained in the mouse with UK Biobank data from healthy and clinical patient data.
The results of the study provide an important basis for research into new previously unknown risk genes for heart disease.
Spielmann, N., Miller, G., Oprea, T.I. et al. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy. Nat Cardiovasc Res 1, 157–173 (2022). doi.org/10.1038/s44161-022-00018-8